The role of stress in the natural history of major depression has been a subject of intense scrutiny, particularly in light of the 20th century discoveries of some of the biological mediators of stress responses. In this paper we present evidence suggesting the hypothesis that an abnormality in the counterregulation of generalized stress responses underlies critical aspects of the pathophysiology of major depression. In particular, we focus on the role of inadequate glucocorticoid restraint of the central nervous system (CNS) components of the adrenocortical and adrenergic systems, i.e. the corticotropin releasing hormone (CRH) components of the adrenocortical and adrenergic systems, i.e. the corticotropin releasing hormone (CRH) and locus ceruleus-norepinephrine (LC-NE) systems. We believe that this hypothesis not only helps explain many of the observed abnormalities in the syndrome of major depression, but also provides a biological basis for subtyping this syndrome
